Neuropathology and Applied Neurobiology最新文献

Pathogens invade the central nervous system (CNS) and cause infections either through the haematogenous route or via peripheral nerves. Neuroinvasion via peripheral nerves, involving spinal or cranial somatic nerves, is well-established for certain viral encephalitides such as rabies, herpes simplex encephalitis, and poliomyelitis. Advances in understanding emerging and re-emerging viruses that cause epidemic CNS infections have highlighted the growing importance of peripheral nerve pathways in viral neuroinvasion. This review focuses on epidemic viral encephalitides caused by three groups of RNA viruses, viz., enteroviruses (enterovirus A71 and enterovirus D68), orthoflaviviruses (West Nile virus and Japanese encephalitis virus), and severe acute respiratory syndrome coronaviruses (mainly severe acute respiratory coronavirus-2). We examine evidence supporting the hypothesis that peripheral nerve viral transmission may play an increasingly significant if not more critical role than the haematogenous route in neuroinvasion.

Aims: Sarcoendoplasmic reticulum Ca²⁺-ATPase 2 (SERCA2), encoded by ATP2A2, is a key protein involved in intracellular Ca²⁺ homeostasis. The SERCA2a isoform is predominantly expressed in cardiomyocytes and type I myofibres. Variants in this gene are related to Darier disease, an autosomal dominant dermatologic disorder, but have never been linked to myopathy. We describe four patients suffering from a novel myopathy caused by a homozygous missense variant in ATP2A2.

Methods: We studied a family with four individuals suffering from an adult-onset skeletal myopathy. We evaluated the clinicopathological phenotype, muscle imaging, and genetic workup including whole genome sequencing and segregation analysis. SERCA2 expression in skeletal muscle was assessed. Functional studies to evaluate Ca²⁺ handling in patient myotubes in response to electrical stimulation or caffeine exposure were performed.

Results: Four sisters developed slowly progressive proximal weakness in adulthood. Biopsy findings showed small vacuoles restricted to type I myofibres. Ultrastructural analysis showed sarcotubular dilation and autophagic vacuoles. Genome sequencing revealed a homozygous variant in ATP2A2 (c.1117G > A, p.(Glu373Lys)) which segregated with the disease. Immunohistochemistry suggested that there was SERCA2 mislocalisation in patient myofibres. Western blotting did not show changes in the amount of protein. In vitro functional studies revealed delayed sarcoendoplasmic reticulum Ca²⁺ reuptake in patient myotubes, consistent with an altered pumping capacity of SERCA2 after cell stimulation.

Conclusions: We report a novel adult-onset vacuolar myopathy caused by a homozygous variant in ATP2A2. Biopsy findings and functional studies demonstrating an impaired function of SERCA2 and consequent Ca²⁺ dysregulation in slow-twitch skeletal myofibres highly support the pathogenicity of the variant.

Aims: Peripheral artery disease (PAD) reduces blood flow to the legs and causes severe muscle and leg dysfunction for PAD patients. Skeletal muscle contractile function is dependent on the health of the muscle itself and that of the neuromuscular junction (NMJ) on the muscle membrane.

Methods: To determine whether the NMJ, including the motor nerve terminals and nicotinic acetylcholine receptors (nAChR), is damaged in PAD, gastrocnemius muscles were collected from 3 controls and 13 PAD patients to capture images from 331 control NMJs and 512 PAD NMJs.

Results: For the motor nerve terminals, there were more denervated nAChR clusters and fewer nerve terminal occupancies in NMJs in PAD patients, compared with controls. For the nAChR clusters in the NMJs, the area per nAChR cluster was 369.3 ± 6.7 versus 225.2 ± 5.3 μm², the area per fragment was 195.9 ± 9.2 versus 107.1 ± 3.1 μm², the number of fragments per nAChR cluster was 2.3 ± 0.1 versus 3.2 ± 0.1, the nAChR cluster area per endplate area was 75.7 ± 1.6 versus 55.7 ± 1.1%, total distance of fragments per nAChR cluster was 4.6 ± 0.4 versus 8.8 ± 0.8 μm, and the fragmented nAChR clusters were 7.6% versus 21.6% of total nAChR clusters in controls versus PAD patients, respectively (p < 0.05 in all parameters).

Conclusions: Our data demonstrate deterioration of the motor nerve terminals and nAChR clusters, which may compromise neuromuscular transmission, and contribute to the severe leg dysfunction observed in patients with PAD.

Background: Progressive external ophthalmoplegia (PEO) is a classic manifestation of mitochondrial disease. However, the link between its genetic characteristics and clinical presentations remains poorly investigated.

Methods: We analysed the clinical, pathological and genetic characteristics of a large cohort of patients with PEO, based on the type of their mtDNA variations. Eighty-two PEO patients were enrolled and grouped into three categories: mtDNA single large-scale deletions (SLDs), multiple deletions (MulDs) and the m.3243A > G point variant. Patients in the SLD category were further divided into 'common deletion' and 'noncommon deletion' groups based on the presence or absence of a 4977-bp deletion. The mutational load of deleted mtDNA of these patients was comprehensively detected by real-time polymerase chain reaction (RT-PCR).

Results: SLD Patients showed the highest proportion of cytochrome C oxidase-negative (COX-n) fibres on muscle biopsy. The mutational load of deleted mtDNA exhibited an inverse relationship with deletion length and a direct relationship with the COX-n fibre ratio. Compared with patients having noncommon deletions, those with common deletions tend to have other muscle involvement, lower body mass index (BMI) scores (17 ± 3 vs. 22 ± 4 kg/m²), higher mutational load in muscle (63% ± 22% vs. 46% ± 24%), more COX-n fibres (26% vs. 9%, interquartile range [IQR]: 15%-32% vs. 6%-26%) and higher growth and differentiation factor 15 (GDF15) levels (2583 vs. 1472, IQR: 1746-4081 vs. 924-2155 pg/mL). MulDs patients displayed milder symptoms, especially compared to patients with m.3243A > G variant, as indicated by their later age of onset (31 vs. 13, IQR: 27-49 vs. 6-29 years), higher BMI scores (24.0 ± 4 vs. 16.5 ± 3.4 kg/m²), lower lactate (1.6 ± 1.1 vs. 6.3 ± 6.0 mmol/L) levels and lower proportion of ragged-blue fibres (RBFs) (3 vs. 16, IQR: 1%-9% vs. 7%-27%).

Conclusion: The m.3243A > G variant group exhibits more severe symptoms compared to other subgroups, particularly MulDs patients. In the SLD group, those with common deletions experience more severe clinical and pathological manifestations. These findings enhance our understanding of PEO, facilitating its diagnosis, prognosis and genetic counselling.

Aims: Meningiomas are common primary CNS tumours, and their morphological diagnosis is usually straightforward. Their histological grading according to CNS WHO criteria alone provides limited information on recurrence risk. Risk stratification of meningiomas combining WHO grade, methylation class and copy number profile improves prediction of the risk of early recurrence. Because of the frequency of meningiomas in diagnostic practice, applying this prediction algorithm to all meningiomas is financially not viable in most healthcare systems.

Methods: We analysed a retrospective dataset of over 1000 meningiomas from a single centre with methylation arrays to provide guidance on which meningiomas to prioritise for integrated molecular testing and to understand how WHO grades resolve into risk strata.

Results: Approximately 90% of CNS WHO Grade 1 meningiomas were allocated into the methylation class 'benign' and also into a low-risk group. Grade 2 meningiomas were allocated almost equally to either the low-risk (39%) or intermediate-risk groups (46%) but occasionally also to the high-risk group (15%). All grading criteria for CNS WHO Grade 2 meningiomas (brain invasion, mitotic count, cytoarchitectural atypia and histological type) showed a similar risk score distribution as the entire group. Grade 3 meningiomas were allocated to intermediate- (26%) or high-risk groups (74%).

Conclusion: Our data suggest that Grade 2 and 3 meningiomas should be prioritised for methylation profiling. A small proportion of Grade 1 meningiomas may also benefit from integrated molecular analysis, and further research is needed to explore if those histologically benign meningiomas with a predicted increased recurrence risk are associated with distinct demographic or histological characteristics.